The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. Recent efforts toward that end within the Clinical and Translational Neuroscience Branch have been manifold, including studies examining pathophysiology and phenotypic heterogeneity in our patient volunteers, collaborative stem cell studies, and studies focused on genetic and gene-by-environment interactions relevant to schizophrenia pathogenesis. Under this project, we have forwarded comprehensive, multimodal positron emission tomography- and magnetic resonance imaging-based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo (medication-free) conditions. Though this work is necessarily challenging to conduct, we continue to make progress in data collection, which includes characterization of dopamine-dependent mnemonic and reward-related neural responses, striatal presynaptic dopamine synthetic capacity, both D1 and D2/3 receptor availability, and neurocognitive functioning. These studies provide the opportunity to better understand illness-related neurobiology in a clinically meaningful context, while accounting for medication effects, and to define contributors to the considerable illness heterogeneity observed in schizophrenia, which may ultimately lead to the development of precision, personalized clinical care. For instance, in multimodal, longitudinal PET studies of subcortical neurochemistry and neurophysiology in schizophrenia, we have been able to show in a cohort of inpatient participants with schizophrenia spectrum illness that medication-related changes in both striatal basal blood flow and clinical ratings during blinded antipsychotic monotherapy relative to placebo conditions were predicted by the degree of ventral striatal presynaptic dopaminergic tone present. These findings provide new avenues for delineating the neurochemical mechanisms underlying heterogeneity in therapeutic response and form the basis of a number of studies currently underway aimed at discovering pathways between dopaminergic systems and different dimensions of psychopathology. Recognizing both the multifaceted nature of and the interindividual variation in clinical and cognitive domain disruptions in schizophrenia, we have embarked on a series of experiments aimed at parsing variability in both symptoms and neuropsychological performance measurements in order to generate biologically meaningful patient subgroups that might ultimately have implications for targeted treatment in this illness. In cluster analyses of clinical ratings from a large cohort of individuals with schizophrenia, we have identified three reliable clinical subgroups based on symptom profile low-symptom, deficit, and distress groups which demonstrated distinct patterns of clinical illness severity, cognitive functioning and personality ratings (Dickinson et al, 2018) and were consistent with an independent sample of individuals with childhood-onset schizophrenia (Craddock et al, 2018). Furthermore, in the adult sample, these subgroups were distinguished by differential frontoparietal neural recruitment during working memory performance, suggesting that clinical distinctions between these groups extend to neurobiology. The importance of this particular phenotype is evident not only in the large body of prior fMRI and PET experimentation from our group characterizing schizophrenia-associated frontoparietal activation abnormalities, but also in our recent collaborative work by demonstrating diminished recruitment of frontoparietal and striatal networks during working memory in inpatients with child-onset schizophrenia (Loeb et al, 2018). Current work extends this line of research and is aimed at understanding key cognitive developmental phenotypes in schizophrenia. Understanding molecular, genetic and environmental pathways to schizophrenia is another major focus for this project. In light of epidemiological findings of association between obstetric/perinatal complications and schizophrenia risk, we have previously shown that such complications interact with hypoxia-responsive schizophrenia risk genes to affect illness risk. Along with collaborators, we have greatly advanced this work to show that the cumulative effect of the most strongly associated schizophrenia genetic risk loci is greatly amplified in patients with a history of obstetric/perinatal complications (Ursini et al, 2018). In studies incorporating cortical interneurons generated from induced pluripotent stem cells derived from our patient cohorts, we have worked with a team of scientists to identify that such cells show synaptic density and arborization aberrancies in line with concurrent dysregulated expression of protocadherin genes and improved with PKC an enzyme in the protocadherin pathway inhibition. (Shao Z et al, 2019). This exciting work points to novel developmental mechanisms in schizophrenia pathogenesis and merits further investigation. Ongoing work in these directions will prove important for refining models of illness and antipsychotic treatment and will inform novel therapeutic targeting. This work involves the following studies: NCT00942981, NCT00001258, NCT00024622, NCT00004571, NCT00001247,NCT00001486, NCT00044083, NCT00057707